Significance To date, the most effective vaccines against SIV in rhesus monkeys have beenlive, attenuated viruses. These vaccines may not prevent infection with the pathogenic challenge virus, but vaccinated monkeys appear to be protected from simian AIDS. Studies of this protective effect are needed in order to develop an effective HIV vaccine. Objectives 1) long-term study of SIV replication and host immune responses in monkeys vaccinated with live, attenuated SIV, with or without challenge with pathogenic SIV and 2) development of novel SIV vaccine strategies that mimic the effects of attenuated virus. Results Three monkeys inoculated with the nonpathogenic molecular clone, SIVmac1A11, have been observed for up to 9 years for signs of simian AIDS. These animals have not developed clinical signs of disease and have maintained normal T lymphocyte counts. However, isolation of SIV from peripheral blood or lymph node has occurred at a very low, intermittent rate during this time. This indicates that the infection with an attenuated strain of SIVmac can be persistent, although at a very low level, and reversion to wild-type virulence has not occurred. Three monkeys that were originally inoculated with a partially attenuated molecular recombinant containing the genome of pathogenic SIVmac239, except for the envelope gp120 which was derived from attenuated SIVmac1A11, developed a low-level persistent viremia and resistance to challenge with pathogenic SIV. These animals have remained clinically healthy, with normal T lymphocyte counts, up to 4 1/2 years after pathogenic virus challenge. The monkeys have maintained low-level persistent infection with SIV, and one animal progressed to simian AIDS at 4 1/2 years post challenge. Future Directions Analysis of a novel cell-mediated immune response that may be protective in an SIV vaccine, delayed type hypersensitivity. Is this response elicited by attenuated SIV or by immunization with antigen-pulsed dendrtitc cells? KEYWORDS molecular clones of simian immunodeficiency virus, attenuation, vaccine;